ABSTRACT The American Cancer Society reports that this year more Americans will die of lung cancer than from any other type of cancer. Non-small cell lung cancers (NSCLC) makes up 85% of lung cancer cases, consisting of lung adenocarcinomas (LUAD), squamous cell, and large cell carcinomas. LUAD is the most common subtype of NSCLC. The five-year survival rate for NSCLC is less than fifteen percent. Late-stage diagnosis and high frequency of cancer metastasis are directly linked to the poor clinical prognosis for NSCLC. Thus, it is imperative to gain a better understanding of the cellular processes that govern NSCLC development and metastasis to improve therapeutic intervention. Although LUAD are typically polygenic, it is recognized that the TP53 tumor suppressor and KRAS proto-oncogene are among the most frequently mutated genes. Despite this understanding, the critical gene targets that become misregulated following alterations in p53 and KRAS remain poorly understood. In this proposal we provide evidence that the KLF6 transcription factor is elevated in LUAD tumors caring mutations in gene encoding p53 (TP53) and KRAS. Elevated KLF6 correlates with poor clinical 5-year survival rates in LUAD. Importantly, our preliminary studies indicate that KLF6 is required to promote cell proliferation in LUAD cells lacking functional p53. Based on our results, we hypothesize that elevated levels of KLF6 are critical to promote cell-cycle progression in LUAD. Experiments in Aim 1 will determine whether human LUAD tumors carrying driver-mutations in TRP53 and KRAS concomitantly overexpress KLF6, and will identify KLF-regulated genes responsible for inappropriate cell proliferation. Aim 2 will determine whether KLF6 is required for tumorigenic properties of LUAD and will utilizes KRASLSL-G12D x TP53 conditional mice to examine whether KLF6 expression is critical for lung cancer development. Experiments outlined in this proposal will determine whether KLF6 functions as a growth-promoting oncoprotein by directly testing the hypothesis that KLF6-dependent gene products are required for inappropriate proliferation in the development and progression of lung cancer.